Preparation of pharmaceutical and other matrix systems by solid-state dissolution

ABSTRACT

A method is disclosed for preparing pharmaceutical and other matrix systems that comprises solidifying a matrix composition dissolved or dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix components being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a usable matrix.

This application is a continuation-in-part of copending U.S. patentapplication Ser. No. 07/454,938, filed Dec. 22, 1989, now abandoned, theentirety of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods for preparing products byremoval of a solid frozen solvent from a frozen matrix mixture.

2. Description of the Background Art

Freeze-drying, i.e., lyophilization, is a well known method of dryingheat-sensitive materials in order to protect them from thermal damage.In the past, preparations containing active ingredients, such aspharmaceuticals, nutrients, diagnostics, fertilizers, and insecticides,have been prepared by freeze-drying aqueous solutions or suspensionscontaining these bioactive ingredients. Conventional methods offreeze-drying or lyophilization involve the freezing of a material at avery low temperature followed by a dehydration by sublimation under highvacuum. These conventional techniques generally employ expensive, bulkyand specially designed lyophilization equipment.

One problem that has arisen, however, with the use of conventionalfreeze-drying processes is cracking of the freeze-dried preparations.Typically, cracking is caused by the stresses set up during icecrystallization. Though cracking is never desirable, it is especiallyundesirable where drop methods of freezing are employed. In such cases,cracking of the frozen droplets usually results in unusable andinelegant remnants of fractured droplets.

Another problem encountered by use of known freeze-drying methods is aphenomenon called meltback. Meltback occurs when the heat requiredduring the drying process melts the frozen material. As such, meltbackdefeats the whole purpose of freeze-drying--the removal of water throughsublimation as opposed to evaporation. To avoid meltback in conventionalfreeze-drying methods, only limited amounts of materials of limitedthickness can be dried at one time or, alternatively, very lowtemperatures have to be used, thereby considerably extending the timerequired for sublimation. Even with these limitations, conventionalfreeze-drying methods are not always sufficient to prevent meltback.

Yet another problem inherent in conventional freeze-drying methods is alack of resistance to disintegration in freeze-dried materials, i.e.,they have little strength. Freeze-drying methods generally yieldproducts that merely crumble when handled. Various freeze-drying andpackaging methods have been employed in attempts to circumvent thisproblem. For example, U.S. Pat. No. 4,305,502 describes a method forforming a shaped article by a lyophilization process in a depression ina sheet of film material. However, such packaging techniques do notavoid the problems posed by conventional freeze-drying methods; thetablets are still susceptible to crumbling if transferred to otherpackaging.

In the area of pharmaceuticals, known freeze-dried dosage forms do notalways exhibit fast dissolution rates when brought into contact withappropriate solvents, such as water, saliva or gastrointestinal fluids.Rapid dissolution of pharmaceutical dosage forms can be of criticalimportance in instances where it is desirable that the pharmaceuticalenter the physiological system as soon as possible.

For example, many individuals, particularly pediatric and geriatricpatients, experience difficulty and discomfort in swallowing solid, slowdissolving tablets and capsules. Similar difficulties are encounteredwhen administering pharmaceuticals orally to animals in the veterinarytreatment of those animals.

Various methods for freeze-drying pharmaceutical dosage forms bylyophilization have been developed to provide fast dissolving dosageforms. U.S. Pat. Nos. 2,166,074; 3,234,091; 4,371,516 and 4,302,502 andUnited Kingdom Patents No. 698,767 and 1,310,824 are all concerned withfreeze-dried dosage forms that are able to dissolve rapidly. Inaddition, Davies, in U.S. Pat. No. 4,642,093, teaches a procedure forpreparing a freeze-dried (lyophilized) foam dosage form usingconventional lyophilization techniques that results in rapidlydissolving pharmaceutical dosage forms.

Yet another problem intrinsic to conventional lyophilization methods isthe lack of uniform porosity in the lyophilized product. Uniformporosity in a lyophilized product is critical for post-loading a dosageform with an active agent.

Thus, there is a need for a method of producing a dosage form similar tothat produced by lyophilization that will avoid cracking and meltback.Furthermore, there is a need for methods of producing pharmaceuticaldosage forms having adequate strength, porosity and exhibiting a fastspeed of dissolution upon ingestion.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an inexpensivemethod of removing solid solvent from a solidified mixture that preventsor reduces the incidence of cracking of the final preparation.

It is an additional object of the present invention to provide a methodof removing solid solvent from a solidified mixture wherein theincidence of meltback during the process is reduced or eliminated.

It is a further object of the present invention to provide a method ofremoving solid solvent from solidified pharmaceutical mixtures so thatthe prepared dosage forms exhibit rapid dissolution in appropriatesolvents.

It is another object of the present invention to provide a method ofpreparing a dosage form having uniform porosity.

It is a further additional object of the present invention to providedosage forms that include active ingredients, such as pharmaceuticals,nutrients, diagnostics, confectioneries, fertilizers and insecticides.

It is yet another object of the present invention to provide a method ofpreparing a dosage form having adequate strength for handling.

It is a specific object of the present invention to provide asolid-state dissolution method of removing solid solvent from solidifiedsamples. According to the inventive method, one or more delivery matrixforming agents (and optionally a sample to be delivered) are dissolvedor dispersed in a first solvent, solidified and subsequently contactedwith a second solvent at a temperature at or higher than thesolidification point of the second solvent and at a temperature at orlower than the solidification point of the first solvent. The firstsolvent in the solidified state is substantially miscible with thesecond solvent, while the matrix forming agent(s) (and sample ifpresent) are substantially insoluble in the second solvent. The firstsolvent is thereby substantially removed from the solidified matrixyielding a solid matrix (optionally containing the sample) substantiallyfree of the first solvent.

It is an additional specific object of the present invention to providea solid-state dissolution method for preparing unit dosage forms whereina first solvent is removed from the dosage form while it is still in thesolid state. According to this inventive method, one or more matrixforming agents (and optionally a sample to be delivered) are dispersedor dissolved in a first solvent and a unit volume of the solution ordispersion is then solidified. The solidified unit volume of sample isnext contacted with a second solvent, which is substantially misciblewith the first solvent in the solidified state. The second solvent is ata temperature at or higher than the solidification point of the secondsolvent and at a temperature at or lower than the solidification pointof the first solvent, the matrix forming agent (and sample if present)being substantially insoluble in the second solvent. Thus, the firstsolvent is substantially removed from the solidified unit volumeyielding a dosage form unit (containing a unit dosage amount of thesample if present) that is substantially free of the first solvent. Inone alternative, the processed dosage form may be contacted with abioactive agent to yield a dosage form having a specific amount of thebioactive agent dispersed therethrough.

It is a further object of the present invention to provide a solidcarrier system for chemicals that a user may add to a medium toinstantaneously obtain a solution or dispersion of desiredconcentration.

The method of the present invention produces dried samples with minimalcracking or meltback of the processed sample.

The resulting preparations exhibit uniform high porosity while havingsufficient strength, i.e., resistance to disintegration or crumblingunder normal manufacturing and handling conditions.

It is another object of the present invention to provide improved dosageforms containing amino acids having from 2 to 12 carbon atoms as matrixforming agents. In a particularly preferred embodiment, glycine forms aprimary part of the matrix of the porous dosage form. This aspect of thepresent invention provides improved dosage forms having the followingadvantages: quick dissolution and disintegration, pleasant taste andmouthfeel, nutrional value, low calorie content and noncariogenicity.

In the realm of pharmaceutical use, pharmaceutical dosage forms preparedaccording to the present invention exhibit rapid dissolution uponcontact with physiological solvents, such as water, saliva, orgastrointestinal fluids. Therefore, the present inventive pharmaceuticaldosage forms provide a more rapid dispersion of the pharmaceuticalwithin the body upon ingestion.

Embodiments of the present invention have the following potentialapplications:

PHARMACEUTICAL

1.Dosage forms having mucoadhesive properties.

2. Dosage forms designed to deliver drug at a controlled rate.

3. Dosing units designed to deliver drugs in the eye.

4. Dosing units designed to deliver drugs in vaginal, rectal and otherbody orifices.

5. Solid dosage forms designed to replace liquid formulations.

6. Dry medicated preparations for topical application after resolvation(reconstitution).

7. Preparation of medicated units or sheets for topical application.

8. Preparation of more palatable dosage forms of drugs that exhibitdisagreeable organoleptic properties.

9. Dosage forms for oral delivery of drugs to persons who havedifficulty swallowing tablets or capsules.

FOOD

1. Preparation of and presentation of dried products composed of foodmaterials.

2. To provide a method for the selective extraction of a material in thesolid form during the drying process.

3. Preparation of confectionery products.

4. Preparation of dosing units for the purpose of modifying properties(e.g. taste, color etc.) or quality of drinking water.

VETERINARY

1. Preparation of dosing units for veterinary use.

2. Preparation of aquarium care and feed products.

COSMETICS

1. Preparation of dry systems for medical and cosmetic use afterresolvation.

DIAGNOSTIC

1. Enzyme/cofactors and biochemical carrier systems.

SANITARY

1. Preparation of dosing units for water purification.

2. Preparation of fragrance carrier units for personal, household andindustrial use.

OTHER

1. Reconstitutable carrier units for pigmented application for paint andother artistic uses.

2. Agriculture and horticulture products requiring release of activeingredients in the presence of water or rain.

3. Preparation of easily removable mold or model material.

4. Preparation of easily removable space maintenance and/or alignmentaid for construction or manufacturing.

Further objects and embodiments of the present invention will be madeknown in the following description of the preferred embodiments andclaims. Though the following description of the preferred embodimentsfocuses on the inclusion of pharmaceuticals as the active agents, it isto be understood that the desirable properties of the inventive methodsand dosage forms may be advantageously used in connection with manydifferent types of active agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The inventive solid-state dissolution method for preparing deliverymatrices and dosage forms begins with a mixture of at least one matrixforming agent in a first solvent. This mixture may be aqueous in natureand may contain various chemicals, drugs and adjuvants in a suitablefirst solvent. The resulting mixture is cooled at a controlled rateuntil completely solidified, and subsequently immersed into a suitablesecond solvent at a temperature below the melting point of the firstsolvent. The solidified first solvent substantially dissolves into thesecond solvent and produces a solid product essentially free of thefirst solvent as a matrix and any chemicals or drugs present in theoriginal mixture. Residual second solvent may be evaporated subsequentto removing the matrices from the second solvent bath. Alternatively,residual second solvent may be removed by contacting the sample with oneor more additional solvents having greater volatility than the secondsolvent.

The various ingredients that may be incorporated into the initialmixture may include matrix forming agents and secondary components.Matrix forming agents suitable for use in the present invention includematerials derived from animal or vegetable proteins, such as thegelatins, dextrins and soy, wheat and psyllium seed proteins; gums suchas acacia, guar, agar, and xanthan; polysaccharides; alginates;carboxymethylcelluloses; carrageenans; dextrans; pectins; syntheticpolymers such as polyvinylpyrrolidone; and polypeptide/protein orpolysaccharide complexes such as gelatin-acacia complexes.

Other matrix forming agents suitable for use in the present inventioninclude sugars such as mannitol, dextrose, lactose, and galactose;cyclic sugars such as cyclodextrin; inorganic salts such as sodiumphosphate, sodium chloride and aluminum silicates; and amino acidshaving from 2 to 12 carbon atoms such as glycine and 1-alanine. Personshaving skill in the art will recognize other acceptable matrix formingagents that may be employed in the present invention.

One or more matrix forming agents may be incorporated into the solutionor suspension prior to solidification. The matrix forming agent may bepresent in addition to a surfactant or to the exclusion of a surfactant.In addition to forming the matrix, the matrix forming agent may aid inmaintaining the dispersion of any active ingredient within the solutionor suspension. This is especially helpful in the case of active agentsthat are not sufficiently soluble in water and must, therefore, besuspended rather than dissolved.

Secondary components such as preservatives, flavors, antioxidants,surfactants, sweeteners, or colorings may also be incorporated in theformulation. Other secondary components include the active or bioactiveagents to be dosed or delivered. These active agents may includepharmaceuticals, nutrients, vitamins, minerals, diagnostics, fertilizersand insecticides. Examples of pharmaceutical agents that may beincorporated in the initial mixture are chlorpheniramine maleate,pseudoephedrine, dextromethorphan, meclizine dihydrochloride,haloperidol, albuterol sulfate, dimenhydrinate, and benzodiazepines suchas diazepam, lorazepam and congeners thereof. However, virtually anypharmaceutical agent may be used in connection with the presentinvention, either by adding the pharmaceutical to the mixture to besolidified or by post loading the pharmaceutical onto a preformedplacebo delivery matrix or dosage form.

The speed in which the sample prepared by the inventive method dissolvesis dependent in large part on the choice of matrix forming agent(s) andtheir concentration. Compounds (either alone or in combination) that canbe used as a matrix forming material for producing placebos or matricesare as follows:

1. Hydroxyethylcellulose

2. Sodium carboxymethylcellulose

3. Microcrystalline cellulose

4. Corn syrup solids

5. Maltrins (maltodextrins)

6. Polydextroses

7. Pectins

8. Carrageenan

9. Agar

10. Chitosan

11. Locust bean gum

12. Xanthan gum

13. Tragacanth

14. Guar gum

15. Konjac flour

16. Rice flour

17. Wheat gluten

18. Sodium starch glycolate

19. Gelatin (pharmaceutical or food grade)

20. Soy fiber protein

21. Potato protein

22. Papain

23. Horse radish peroxidase

24. Glycine

25. Mannitol

Preferred matrix forming agents include pharmaceutical grade gelatins,pectins (nonhydrolyzed, partially hydrolyzed or hydrolyzed), glycine andmannitol, either alone or in combination. Various concentrations ofmatrix forming agents may be used in the present invention. Preferredconcentrations of matrix forming agents in a suitable solvent are about0.1 to 15% weight/weight (w/w). A more preferred concentration is about0.5 to 4% (w/w). Optimum results are obtained from the present inventivemethod in pharmaceutical applications when an approximately 2%weight/weight aqueous solution of the matrix forming agent(s) is used.

The concentrations of secondary components incorporated in the initialmixture are limited primarily by the solubility of the secondarycomponent(s) in the solvent used to dissolve the component. Theconcentration required is defined by the amount of agent to beincorporated in the dosage form. Therefore, concentrations of thesecomponents in the initial mixtures may range from about 0.0001 to 20%.

Various solvents may be employed in the present invention. A firstsolvent must be chosen that will dissolve and/or disperse the matrixforming agents, and other miscellaneous agents of the sample.Furthermore, the first solvent must be such that it has a solidificationpoint higher than the solidification point of the second solvent. Apreferred first solvent is water; other suitable first solvents includepolyethylene glycols, carboxypolymethylenes, tert-butyl alcohol,acetonitrile, acetamide and phenol. A first solvent may comprise asuitable combination of any of these solvents, such as, for example, awater:tert-butyl alcohol solvent mixture.

The second solvent should desirably act as a solvent for the solidifiedfirst solvent. It is advantageous that the dissolution solvent also havea solidification point below the solidification point of the firstsolvent. When a substantially dry sample, placebo or dosage form isdesired, it is advantageous that the second solvent have a relativelylow boiling point or relatively high vapor pressure such that the secondsolvent evaporates quickly from the processed sample. Therefore,preferred second solvents will have boiling points or vapor pressuressuch that the solvent evaporates readily at atmospheric pressure or atreduced pressure. Preferred second solvents for use with water as thefirst solvent include materials which are water miscible. Thesematerials may be used in the solid, liquid or gaseous state.

However, those skilled in the art will appreciate that various solidsample formulations may be desired that are not dry but have substantialamounts of liquid dispersed throughout. Hence, a solvent having arelatively high boiling point such as, for example, dimethylformamide orethylene glycol, could be employed as the second solvent.

It is advantageous that the dosage form components (matrix formingagents and secondary components) be substantially insoluble in thesecond solvent, i.e., the second solvent will not dissolve the samplecomponents. Hence, depending on these components, acceptable secondsolvents include methanol, ethanol, acetone, water, isopropyl alcohol,methyl isobutyl ketone and liquid carbon dioxide. Various mixtures ofthese solvents may comprise the second solvent of the present invention.

Various combinations of first solvent:second solvent may be employed inthe present invention. A preferred first solvent:second solvent systemfor pharmaceutical purposes is water:absolute ethanol. Other systems maybe chosen based on the sample components to be processed. Therefore,other suitable first solvent:second solvent systems include tert-butylalcohol:water; acetamide:methanol; phenol:isobutyl ketone andpolyethylene glycol:alcohol, among others.

The mixtures of sample components to be solidified may be in a varietyof forms. They may be solutions, suspensions, dispersions, emulsions, orfoams. Persons having skill in the art will recognize acceptable methodsfor preparing each of these. A foam sample may be prepared by dispersinga gas in a liquid. A preferred method for preparing such a foam isdescribed by Davies in U.S. Pat. No. 4,642,903, the entirety of which isincorporated herein by reference.

The mixture may be solidified by any conventional cooling process. Forexample, the mixture may be solidified by dispensing it into preformedmolds and subsequently cooling such molds on refrigerated shelves or inrefrigerated chambers. Alternatively, the molds containing the mixturemay be passed through a stream of cold gas or vapor, such as liquidnitrogen in a freezing tunnel. A preferred method for solidifying themixtures in the molds is to surround the molds in dry ice until themixture has solidified.

As an alternative to the use of molds, the mixtures may be solidified indropwise fashion. For example, the mixture may be pumped or fed undergravity through an orifice in order to form drops, spheres or a spray ofsmall particles. These drops can then be solidified by passage through acold gas or liquid, for example, liquid nitrogen or liquid nitrogenvapor. Another possibility is that drops of the mixture may besolidified in a chilled liquid that is immiscible with the mixture. Insuch cases, the relative densities of the liquid and the mixture arecontrolled such that the drops can either pass through the chilledimmiscible liquid as they solidify or, alternatively, the solidifieddroplets may float on the surface of the chilled immiscible liquid. Thislatter flotation feature facilitates the collection of the solidifieddroplets. An example of a liquid that may be chilled and that isimmiscible with most primarily aqueous mixtures is trichloroethylene.

The resulting solidified mixture is contacted in the second solventwhereby the solidified first solvent dissolves into the second solvent.The contact time depends upon the amount of first solvent to bedissolved from the solidified mixture. This in turn is related to thesize of the solidified mixture. The time required is further related tothe temperature of the second solvent.

It is advantageous that the second solvent be at a temperature lowerthan the solidification point of the first solvent. For applicationsusing a water:ethanol system the temperature of the second solvent maybe about 0° to -100° C. A preferred temperature for this system is about-4° to -20° C.

In other systems, it is preferred that the second solvent be at atemperature of about 1° to 100° C. below the solidification point of thefirst solvent. A more preferred temperature for the second solvent isabout 4° to 20° C. below the solidification point of the first solvent.At these temperatures, the amount of second solvent required to dissolvefirst solvent should be about 2 to 40 times the total weight of deliverymatrices or dosage forms to be processed.

A preferred weight of second solvent for use at a temperature of about10° to 20° C. below the melting point of the first solvent is about 4 to6 times the total weight of the dosage form or matrix to be processed.

A preferred amount of ethanol for use at -4° to -20° C. is about 20times the weight of samples to be processed. For example, to process 40l ml matrices, about 800 gm of ethanol would be used. When thesepreferred temperatures and weights of second solvent are employed, thecontact times of matrix with second solvent are about 1 to 20 hours. Acontact time of about 2 to 10 hours is preferred for a water:ethanolsystem. For large sizes, longer contact times are necessary. Thesepreferred contact times and temperatures afford maximum strength andporosity of the processed formulation.

Various methods exist for contacting the frozen dosage unit/matrix withthe second solvent. These include immersing the formulation into asolvent bath and spraying the formulation with the solvent. A preferredmethod of contacting the solidified mixture with the second solvent isimmersion.

Intimate contact of the second solvent with the dosage form can beassured by continuous or intermittent mixing of the second solvent withthe sample or pumping of the second solvent through a vessel containingthe sample with or without recirculation of the second solvent.Alternatively, microwave assistance may be used to facilitatedissolution of the first solvent.

Removal of the resulting processed sample or product from the secondsolvent yields a sample or dosage form having uniform porosity and highresistance to crumbling. The product or formulation may be immediatelyused, packaged, or stored.

Alternatively, any residual second solvent may be removed by placing theproduct in a vacuum chamber under reduced pressure, exposing a volatilesecond solvent to the atmosphere at normal or elevated temperatures, orpassing a stream of air or nitrogen over the sample at normal orelevated temperatures with our without recirculation. Alternatively,microwave assisted drying may be used.

In another embodiment, the product may be contacted with a third solventto remove any residual second solvent. It is advantageous that the thirdsolvent is a solvent having greater volatility than the second solventsuch that it will readily evaporate from the product. This third solventadvantageously will be substantially immiscible with the productconstituents.

Formulations containing an active agent such as a chemical or drug thatis insoluble in the second or dissolution solvent may be prepared bydirectly adding the agent to the dispersion or solution to besolidified. However, active agents that are substantially soluble in thesecond solvent should desirably not be added to the initial mixturebecause some portion of this chemical or drug may be lost to the secondsolvent upon dissolution of the first solvent into the second solvent.Therefore, dosage forms or matrices having such chemicals or drugs maybe advantageously prepared by first preparing a placebo or blank dosageform and subsequently contacting that dosage form with a specific amountof the active agent in a unit volume of a suitable solvent. These activeagents may be loaded or dosed on the placebo as a solution, suspension,dispersion or emulsion of the agent in a carrier solvent immiscible withthe placebo materials. Thus, the active agent will be substantiallydistributed throughout the placebo.

The carrier solvent is then allowed to evaporate at normal pressure andnormal or elevated temperatures, by passing a stream of air or nitrogenover the dosage form at normal or elevated temperatures, or by placingthe dosage form in a vacuum chamber under reduced pressure and normal orelevated temperatures. Alternatively, microwave assisted drying may beused. Alternatively, the dosage form may be placed in a vacuum chamberto remove the residual carrier solvent.

The active agents that may be post loaded on the placebo or blankinclude the secondary components that may be added to the initialmixture to be processed. The concentration of these agents in the postloading solution is defined by the amount of agent desired in the finalprocessed dosage forms. These concentrations are only limited by thesolubility of the agent in the post loading solvent, although the use ofserial post loading and/or suspensions can overcome most solubilitylimitations. Accordingly, the concentration of the active agent mayrange from about 0.0001% to 20% or more.

The concentration of active agent in the final dosage form prepared byeither method, i.e., post loading or conventional premixing, is relatedto the amount of active agent desired to be delivered in the processeddosage form. This concentration is limited by the solubility of theactive agent in the solvent, although dosage forms may be seriallyprocessed with multiple post loadings in order to increase theconcentration to a desirable level. In addition, suspensions of theagent(s) may be used to post load the placebo. Accordingly, theconcentration of active agent in the final matrix or dosage form mayrange from less than 0.01% to more than 300% of the weight of the dosageform.

Dosage forms may be prepared in a wide variety of sizes through use ofthe present invention, ranging from about 0.25 ml to 30 ml and larger.Large dosage forms may be advantageously prepared by the presentinvention without the long drying times required by lyophilization.

In another preferred embodiment of the present invention, one or moresmall amino acids having from 2 to 12 carbon atoms are used as a matrixforming agent. Glycine and 1-alanine are the particularly preferredamino acids for this purpose. The amino acid(s) should preferably bepresent in concentrations of about 0.1% to 100% (w/w) of the totalsolids content in the initial solution and/or concentrations of about0.1% to 100% (w/w) of the total solids content in the final dosage form.Embodiments containing glycine or other small amino acids may beprocessed by the solid-state dissolution procedures disclosed herein orby conventional lyophilization techniques well known to those of skillin the art. The resulting dosage forms have a porous network of matrixmaterial and rapidly disintegrate in water in less than about 10seconds. Active agents may be incorporated into these dosage forms bythe methods disclosed herein.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures described in them.

EXAMPLE 1 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Gelatin (pharmaceutical grade) (20 g) and mannitol (30 g) were dissolvedin 950 g of water with heating and constant stirring. The resultingsolution was carefully transferred into 1 ml size molds. A moldconsisted of a polyvinyl chloride (p.v.c.) sheet with 50 cylindricaldepressions (18 mm diam. and 5 mm deep). The p.v.c. sheet and itscontents were cooled with dry ice for about one hour or frozen quicklyin a cold gas freezing tunnel. The frozen contents were weighed andimmersed into 5000 g of absolute ethanol at -15° C. Each frozen sampleweighed 1.00 g. When all the ice was dissolved into the ethanol (5hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 2 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Gelatin (pharmaceutical grade) (20 g) and mannitol (30 g) were dissolvedin 950 g of water with heating and constant stirring. The resultingsolution was carefully transferred into 1 ml size molds. A moldconsisted of a polyvinyl chloride (p.v.c.) sheet with 50 cylindricaldepressions (18 mm diam. and 5 mm deep). The p.v.c. sheet and itscontents were cooled with dry ice for about one hour or frozen quicklyin a cold gas freezing tunnel. The frozen contents were then weighed andimmersed into 5000 g of methanol at -15° C. Each frozen sample weighed1.0 g. When all the ice was dissolved into the methanol the product wastransferred to a vacuum chamber in order to remove residual methanol.This produced a sample, i.e., a network of carrier material, thatdisintegrated rapidly in 1 to 5 seconds when taken orally. Eachresulting processed placebo weighed 50 mg.

EXAMPLE 3 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Gelatin (pharmaceutical grade) (20 g) and mannitol (30 g) were dissolvedin 950 g of water with heating and constant stirring. The resultingsolution was carefully transferred into 1 ml size molds. A moldconsisted of a polyvinyl chloride (p.v.c.) sheet with 50 cylindricaldepressions (18 mm diam. and 5 mm deep). The p.v.c. sheet and itscontents were cooled with dry ice for about one hour or frozen quicklyin a cold gas freezing tunnel. The frozen contents were then weighed andimmersed into 5000 g of acetone at -15° C. Each frozen sample weighed1.0 g. When all the ice was dissolved into the acetone the product wastransferred to a vacuum chamber in order to remove residual acetone.This produced a sample, i.e., a network of carrier material, thatdisintegrated rapidly in 1 to 5 seconds when taken orally. Each of theprocessed samples weighed 50 mg.

EXAMPLE 4 Preparation of a Placebo Carrier Matrix Containing a Sweetener

Gelatin (pharmaceutical grade) (20 g), mannitol (30 g), and aspartame(20 g) were dissolved in 930 g water with heating and constant stirring.The resulting solution was transferred accurately into 1 ml size molds.Placebo samples were prepared using the method described above inExample 1. This produced a network of the carrier material and aspartamethat disintegrated rapidly, in 1 to 5 seconds, when taken orally. Eachof the processed aspartame containing samples weighed 70 mg.

EXAMPLE 5 Preparation of a Pharmaceutical Dosage Form by Post-Loadingthe Active Agents

A placebo carrier material was prepared to contain aspartame asdescribed above in Example 4. A 100 ml solution was prepared to contain0.5 g chlorpheniramine maleate, 7.5 g pseudoephedrine HCl, 0.19 gmethylparaben, 0.063 g propylparaben, 0.1 g menthol, 0.1 ml eucalyptusoil, 0.2 ml peppermint oil, 5.0 g PVP-10, 0.35 g magnasweet 136, 0.25 gmagnasweet 110, and 0.20 g of citric acid in absolute ethanol. A 0.20 mlaliquot of the resulting ethanol solution was then carefully loaded onthe placebo carrier material. The solvent was allowed to evaporate undervacuum for one hour. The resulting dry dosage form dissolves rapidly inwater and also in the mouth. Each unit of dosage form contained 15 mg ofpseudoephedrine HCl and 1 mg of chlorpheniramine maleate. The totalweight of the dosage form was 90 mg.

EXAMPLE 6 Preparation of a Colored Placebo Carrier Matrix Containing aDye

Gelatin (pharmaceutical grade) (20 g), mannitol (30 g) and FD&C yellow#5 (0.1 ml) were dissolved in 949.9 g water with heating and constantstirring. The resulting solution was transferred carefully into 1 mlsize molds. Placebo samples were prepared as described above inExample 1. This produced a network of a yellow colored carrier materialthat disintegrated rapidly, in 1 to 5 seconds, when taken orally. Themethod was repeated with several pharmaceutically acceptable watersoluble dyes. Each resulted in a dosage form that weighed 50 mg anddissolved in 1 to 5 seconds upon oral administration.

EXAMPLE 7 Preparation of a Placebo Carrier Matrix Containing ADispersion of Water Insoluble Pigment

Gelatin (pharmaceutical grade) (20 g) and mannitol (30 g) were dissolvedin 947 g water with heating and constant stirring. 3 g of an 8-10%dispersion or lake of FD&C yellow #5 was added to the solution withconstant stirring. The resulting suspension was sonicated until thepigment was uniformly dispersed. The suspension was then transferredcarefully into 1 ml size molds. Placebo samples were then prepared fromthe suspension as described above in Example 1. This produced a networkof a yellow colored carrier material that disintegrated rapidly, in 1 to5 seconds, when taken orally. The method was repeated with severalpharmaceutically acceptable water insoluble lake pigments. Each resultedin a placebo sample that weighed 50 mg and dissolved in 1 to 5 secondsupon oral administration.

EXAMPLE 8 Preparation of a Pharmaceutical Dosage Form Containing anActive Agent By Post-Loading a Colored Processed Matrix

A 100 ml solution was prepared to contain 3.75 g pseudoephedrine HCl,0.25 g chlorpheniramine maleate, 1.25 g dextromethorphan, 0.50 g sodiumsaccharin, and 0.10 g of menthol in absolute ethanol. A colored placebowas prepared as described above in Example 6. To this placebo was added0.20 ml of the solution and the solvent was subsequently allowed toevaporate in a vacuum chamber for one hour. The resulting dry dosageform dissolves rapidly in water and also in the mouth. Each dosage unitweighed 62 mg and contained 7.5 mg of pseudoephedrine HCl, 0.5 mg ofchlorpheniramine maleate and 2.5 mg of dextromethorphan HBr. Severaldoses of above three drugs were prepared with different flavor systemssuch as grape, punch, lemon-lime, raspberry and cherry. Each resulted ina unit dosage form that dissolved rapidly in 1 to 5 seconds when takenorally.

EXAMPLE 9 Preparation of a Pharmaceutical Dosage Form Containing anActive Agent By Post-Loading A Processed Matrix

A placebo sample was prepared as described above in Example 1. To thisplacebo sample was added 0.2 ml of a solution prepared to contain 15.0 gmeclizine HCl, 0.1 g menthol, 1.25 g aspartame, 0.1 ml raspberry flavorin sufficient 1:1 chloroform:isopropyl alcohol to yield 100 ml. Thesolvent was then allowed to evaporate in a vacuum chamber for about onehour. The resulting dosage unit contained 25 mg of meclizine. Severaldoses of meclizine HCl were prepared with different flavor systems suchas grape, punch, lemon-lime, raspberry and cherry. Each resulted in adosage unit that weighed 83 mg and dissolved in 1 to 5 seconds whentaken orally.

EXAMPLE 10 Preparation of a Pharmaceutical Dosage Form ContainingHaloperidol as an Active Agent

A unit dosage was prepared to contain 5 mg of haloperidol by the methoddescribed above in Example 9. A 100 ml chloroform:isopropyl alcoholsolution was prepared to contain 2.5 g of haloperidol prior to treatingthe placebo sample. The resulting dosage forms weighed 61 mg.

EXAMPLE 11 Preparation of a Pharmaceutical Dosage Form ContainingHaloperidol as an Active Agent

A placebo carrier material was prepared to contain aspartame asdescribed above in Example 4. A 100 ml solution was prepared to contain2.5 g haloperidol, 0.35 g magnasweet 136, 0.25 g magnasweet 110, 0.5 mllemon flavor, 0.25 ml orange flavor, and 0.6 g citric acid in warmabsolute ethanol. A 0.20 ml aliquot of the resulting ethanol solutionwas then carefully loaded on the placebo carrier material. The solventwas allowed to evaporate under vacuum for one hour. Each unit of dosageform contains 5 mg of haloperidol.

EXAMPLE 12 Preparation of a Pharmaceutical Dosage Form By Post Loading aPlacebo with a Suspension of Active Agent

A mixture was prepared to contain 2.0 g albuterol sulfate, 0.1 gmenthol, 0.2 g sodium saccharin, and sufficient absolute ethanol to make100 ml of mixture. After stirring this mixture, it was sonicated untilthe albuterol sulfate was uniformly dispersed, and 0.2 ml aliquots ofthe resulting suspension were carefully added to placebo samplesprepared as described above in Example 1. Each resulting dosage unitweighted 55 mg and contained 4 mg of albuterol sulfate.

EXAMPLE 13 Preparation of a Unit Dosage Form of Dimenhydrinate byPost-Loading a Processed Matrix with A Suspension of Dimenhydrinate

A 100 ml solution was prepared to contain 25 g dimenhydrinate inabsolute ethanol. A 0.2 ml aliquot of this solution was then added toplacebo units prepared as described in Example 1. Each resulting dosageunit weighed 100 mg. contained 50 mg of dimenhydrinate, and dissolvedrapidly in the mouth.

EXAMPLE 14 Preparation of a Breath Freshener Formulation

A 100 ml absolute ethanol solution was prepared to contain 0.19 gmethylparaben, 0.063 g propylparaben, 0.1 g menthol, 0.1 ml eucalyptusoil, 0.2 ml peppermint oil, 5.0 g polyvinylpyrrolidone (PVP), 0.25 gmagnasweet 110, 0.35 g magnasweet 136, and 0.20 g citric acid. A 0.20 mlaliquot of the resulting solution was then added to placebo samplesprepared as described in Example 1. The ethanol was allowed to evaporateunder vacuum for one hour. The resulting dry formulations weighed 63 mgand dissolved rapidly in water and also in the mouth.

EXAMPLE 15 Preparation of a Unit Dose of a Low Calorie Sugar SubstituteBy Solid-State Dissolution

Gelatin (pharmaceutical grade) (20.0 g), mannitol (30 g), and aspartame(20.0 g) were dissolved in 930 g of water with heating and constantstirring. The resulting solution was transferred accurately into 1 mlsize molds and solidified. The solid-state dissolution procedure wasperformed as described in Example 1. This produced a network of thecarrier material that weighed 60 mg and disintegrated rapidly, in 1 to 5seconds, when added to a glass of water. The water was found to beconsiderably sweet in taste.

EXAMPLE 16 Preparation of Rapidly Dissolving Unit Dose Of Buffer BySolid-State Dissolution

Gelatin (pharmaceutical grade) (20.0 g), monobasic sodium phosphate(40.0 g), and diabasic sodium phosphate (30.0 g) were dissolved in 910 gwater with heating and constant stirring. Solid-state dissolution wasperformed as described in Example 1 and produced a buffer salt carriersystem. Each resulting buffer product weighed 90 mg and disintegratedinstantaneously when added to water to produce a solution having thedesired specific pH and buffer strength.

EXAMPLE 17 Preparation of a Unit Dry Emulsion By Solid-State Dissolution

Gelatin (pharmaceutical grade) (25.0 g), mannitol (30.0 g) and aspartame(5.0 g) were dissolved in 870 g water with heating and constant stirringand the mixture subsequently was maintained at 60° C. A proprietarytriglyceride mixture (70.0 g) and glycerol monostearate (10 g) weremelted together at 60° C. and the molten fatty mixture was added to theaqueous gelatin solution at 60° C. with vigorous stirring. The resultingemulsion was cooled and poured into molds. The solid-state dissolutionmethod of Example 1 was followed to produce dry emulsions weighing 140mg.

EXAMPLE 18 Preparation of a Unit Dosage of a Foam By Solid-StateDissolution

An aqueous solution was prepared to contain 4% by weight gelatin(pharmaceutical grade) and 3% mannitol. To this solution was added 1%sodium diethylsulfosuccinate as a surfactant. Air bubbles wereincorporated into the solution by use of a Silverson homogenizer. All ofthe air bubbles incorporated into the solution were of relativelyuniform size and had an average diameter of approximately 100 microns.The resulting solution was then dispersed dropwise into a flaskcontaining liquid nitrogen. The spheres floated not only duringfreezing, but also continued to float once completely frozen. The frozenspheres were collected and immersed in a bath of absolute ethanol at-15° C. The spheres were removed from the ethanol when the ice hadcompletely dissolved into the ethanol solution. The spheres weresubsequently placed in a vacuum oven to remove residual ethanol. Theresulting processed spheres weighed 50 mg and dissolved rapidly in 1 to5 seconds, when taken orally.

EXAMPLE 19 Preparation of a Placebo Carrier Matrix by Solid-StateDissolution

Pectin (5 g), mannitol (50 g), and aspartame (5 g) were dissolved in 940g of water. The resulting solution was carefully transferred into 1 mlsize molds. A mold consisted of a polyvinyl chloride (p.v.c.) sheet with50 cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the frozen water was dissolved into theethanol (5 hours), the product was transferred to a vacuum chamber inorder to remove residual ethanol. This produced a sample, i.e., anetwork of carrier material, that disintegrated rapidly in 1 to 5seconds when taken orally. Each of the processed samples weighted 50 mg.

EXAMPLE 20 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Pectin (20 g) was dissolved in 980 g of water by heating with constantstirring in a boiling hot water bath for periods of 15 min to four hrs.The resulting solution was then allowed to attain room temperature. To250 g of this solution, 50 g of mannitol, 5 g of aspartame, and 695 g ofwater were added with constant stirring. The mixture was stirred untilmannitol and aspartame dissolved completely.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e. a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 21 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Pectin (20 g) was dissolved in 980 g of water. The resulting solutionwas autoclaved at 121° C. for 15 minutes. The autoclaved solution wasthen allowed to attain room temperature. To 500 g of autoclavedsolution, 50 g of mannitol, 5 g of aspartame, and 445 g of water wereadded with constant stirring. The mixture was stirred until mannitol andaspartame dissolved completely.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 22 Preparation of a Breath Freshener Formulation

A 100 ml absolute ethanol solution was prepared to contain 0.19 gmethylparaben, 0.063 g propylparaben, 0.1 g menthol, 0.1 ml eucalyptusoil, 0.2 ml peppermint oil, 5.0 g polyvinylpyrrolidone (PVP), 0.25 gmagnasweet 110, 0.35 g magnasweet 136, and 0.20 g. citric acid. A 0.20ml aliquot of the resulting solution was then added to placebo samplesprepared as described in Example 19. The ethanol was allowed toevaporate under vacuum for one hour. The resulting dry formulationsweighed 63 mg and dissolved rapidly in water and also in the mouth.

EXAMPLE 23 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Pectin (8 g), microcrystalline cellulose (0.5 g), mannitol (35 g), andaspartame (5 g) were dissolved in 957.5 g of water.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e. a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 35 mg.

EXAMPLE 24 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Pectin (8 g), sodium starch glycolate (0.5 g), mannitol (35 g), andaspartame (5 g) were dissolved in 957.5 g of water.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 36 mg.

EXAMPLE 25 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Maltrin M100 (Maltodextrin DE10) (100 g), mannitol (30 g), and xanthangum (0.5 g) were dissolved in 869.5 g of water.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 26 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

A 10% polydextrose solution (100 g), mannitol (35 g), and aspartame (5g) were dissolved in 860 g of water with heating and constant stirring.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 27 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Locust bean gum (2 g), mannitol (35 g), and aspartame (5 g) weredissolved in 958 g of water with heating and constant stirring.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 28 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Carrageenan (5 g) and mannitol (35 g) were dissolved in 960 g of waterwith heating and constant stirring.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material. Each of the processed samples weighed 50 mg.

EXAMPLE 29 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Konjac flour (5 g), mannitol (35 g), and aspartame (5 g) were added to955 g of water with heating and constant stirring.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 30 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Hydroxyethylcellulose (5 g), mannitol (50 g), and aspartame (5 g) weredissolved in 940 g of water with heating and constant stirring.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diam. and 5 mm deep). The p.v.c. sheetand its contents were cooled with dry ice for about one hour or frozenquickly in a cold gas freezing tunnel. The frozen contents were weighedand immersed into 5000 g of absolute ethanol at -15° C. Each frozensample weighed 1.00 g. When all the ice was dissolved into the ethanol(5 hours), the product was transferred to a vacuum chamber in order toremove residual ethanol. This produced a sample, i.e., a network ofcarrier material, that disintegrated rapidly in 1 to 5 seconds whentaken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 31 Preparation of a Placebo Carrier Matrix by Solid-StateDissolution Using a Dynamic Flow Through System

Gelatin (pharmaceutical grade, 20 g) and mannitol (30 g) were dissolvedin 950 g of water. The resulting solution was carefully transferred into1 ml size molds. A mold consisted of a polyvinyl chloride (p.v.c.) sheetwith cylindrical depressions (18 mm diameter and 5 mm deep).

The p.v.c. sheet with its contents was cooled with dry ice for about onehour, or alternatively quickly solidified in a cold gas freeze tunnel.The frozen contents were weighed and stored at -15° C. Each frozensample weighed 1.00 g.

The flow through system consisted of the following:

1. Primary Reservoir: It consisted of an airtight container of suitablesize that contained open shelved compartments. It served as a reservoirfor frozen tablets during the solid-state dissolution procedure. It alsocontained an air diffuser assembly at the bottom of the container.

2. Secondary Reservoir: It consisted of an airtight container ofsuitable size, which served as a reservoir for ethanol. The ratio ofprimary to secondary reservoir size was about 6:1.

3. Pump and Tubing: The two reservoirs were connected to the pump viasuitable tubing in a closed system.

The primary and secondary reservoirs were maintained at -15° C. Thesolidified tablets were placed in the primary reservoir compartments inone to six tablet layer thicknesses. About 5,000 g of absolute ethanolwere transferred from the secondary reservoir into the primaryreservoir. About 1,000 g of absolute ethanol were pumped into thesecondary reservoir. Ethanol was circulated from the secondary to theprimary reservoir and back to the secondary reservoir at the rate of0.03 l/min to 2 l/min in a closed system. Every one or two hours, thecirculating ethanol was replaced with fresh absolute ethanol. Four tofive batches of fresh absolute ethanol over a period of five to eighthours were found to be adequate to dissolve all the frozen water. Whenall the ice was dissolved into ethanol and the ethanol drained, theprimary reservoir was connected from the bottom to a supply of dry air.The dry air was blown through the air diffuser system into the productuntil the product was completely dry. This produces a sample, i.e., anetwork of carrier material, that disintegrated rapidly in one to fiveseconds when taken orally. Each of the processed samples weighed 50 mg.

EXAMPLE 32 Preparation of a Placebo Carrier Matrix by Solid-StateDissolution Using a Dynamic Flow Through System

Gelatin (pharmaceutical grade, 20 g) and mannitol (30 g) were dissolvedin 950 g of water. The resulting solution was carefully transferred into1 ml size molds. A mold consisted of a polyvinyl chloride (p.v.c.) sheetwith cylindrical depressions (18 mm diameter and 5 mm deep).

The p.v.c. sheet, with its contents, was cooled with dry ice for aboutone hour, or alternatively, quickly solidified in a cold gas freezetunnel. The frozen contents were weighed and stored at -15° C. Eachfrozen sample weighed 1.00 g.

The flow through system consisted of the following:

1. Reservoir: It consisted of an airtight container of suitable size,which contained open shelved compartments. It served as a reservoir forfrozen tablets during the solid-state dissolution procedure. It alsocontained an air diffuser assembly at the bottom of the container.

2. Pump and Tubing: The reservoir was connected to the pump via suitabletubing in a closed system.

The reservoir was maintained at -15° C. The solidified tablets wereplaced in the reservoir in one to six tablet layer thicknesses. About5,000 g of absolute ethanol were filled into the reservoir. The ethanolwas circulated from the top to the bottom of the reservoir at the rateof 0.03 l/min in a closed system. At one or two hour intervals, thesystem was replaced with fresh absolute ethanol. About four to fivebatches of fresh absolute ethanol were found to be adequate to dissolveall the ice. When all the ice was dissolved into ethanol, the reservoir(after draining ethanol) was connected from the bottom to a supply ofdry air. The dry air was blown through the air diffuser system into theproduct until the product was completely dry. This produced a sample,i.e., a network of carrier material, that disintegrated rapidly in oneto five seconds when taken orally. Each of the processed samples weighed50 mg.

EXAMPLE 33 Preparation of a Placebo Carrier Matrix by Solid-StateDissolution Using a Dynamic Flow Through System

Gelatin (pharmaceutical grade, 20 g) and mannitol (30 g) were dissolvedin 950 g of water. The resulting solution was carefully transferred into1 ml size molds. A mold consisted of a polyvinyl chloride (p.v.c.) sheetwith cylindrical depressions (18 mm diameter and 5 mm deep).

The p.v.c. sheet, with its contents, was cooled with dry ice for aboutone hour, or alternatively, quickly solidified in a cold gas freezetunnel. The frozen contents were weighed and stored at -15° C. Eachfrozen sample weighed 1.00 g.

The flow through system consisted of the following:

1. Reservoir: It consisted of an airtight container of suitable size,which contained open shelved compartments. It served as a reservoir forfrozen tablets during the solid-state dissolution procedure. It alsocontained an air diffuser assembly at the bottom of the container.

2. Mixing device: It consisted of suitable mixing apparatus, such aspropeller/shaft type stirrer or magnetic stir bar/stir plate. The mixingdevice was used to provide a homogenous solvent/water mixture.

The reservoir was maintained at -15° C. The solidified tablets wereplaced in the reservoir in one to six tablet layer thicknesses. About5,000 g of absolute ethanol were filled into the reservoir. The ethanolwas agitated by a suitable mixing device.

At one or two hour intervals, the system was replaced with freshabsolute ethanol. About four to five batches of fresh absolute ethanolchanges were found to be adequate to dissolve all the ice. When all theice was dissolved into ethanol, the reservoir (after draining ethanol)was connected from the bottom to a supply of dry air. The dry air wasblown through the air diffuser system into the product until the productwas completely dry. This produced a sample, i.e., a network of carriermaterial, that disintegrated rapidly in one to five seconds when takenorally. Each of the processed samples weighed 50 mg.

EXAMPLE 34 Preparation of a Placebo Carrier Matrix By Solid-StateDissolution

Pectin (20 g) was dissolved in 980 g of water. The resulting solutionwas autoclaved at 121° C. for 15 minutes. The autoclaved solution wasthen allowed to attain room temperature. To 425 g of the autoclavedsolution, 10 g of mannitol, 2.5 g of aspartame, 50 g of glycine and512.5 g of water was added with constant stirring. The mixture wasstirred until mannitol and aspartame dissolved completely.

The resulting solution was carefully transferred into 1 ml size molds. Amold consisted of a polyvinyl chloride (p.v.c.) sheet with 50cylindrical depressions (18 mm diameters and 5 mm deep). The p.v.c.sheet and its contents were cooled with dry ice for about one hour. Atthe end of one hour the frozen contents were weighed and immersed into5000 g of absolute ethanol at -15° C. Each frozen sample weighed 1.00 g.When all the ice was dissolved into the ethanol (5 hours), the productwas transferred to a vacuum chamber in order to remove residual ethanol.This produced a sample, i.e., a network of carrier material, thatdisintegrated rapidly in 1 to 5 seconds when taken orally. Each of theprocessed samples weighed 70 mg.

EXAMPLE 35 Preparation of a Placebo Carrier Matrix by Solid-StateDissolution

Gelatin (pharmaceutical grade) (20 g), glycine (30 g), and aspartame(2.5 g) were dissolved in 940 g of water. The resulting solution wascarefully transferred into 1 ml size molds. A mold consisted of apolyvinyl chloride (p.v.c.) sheet with 50 cylindrical depressions (18 mmdiameter and 5 mm deep). The p.v.c. sheet and its contents were cooledwith dry ice for about one hour. At the end of one hour, the frozencontents were weighed and immersed into 5000 g of absolute ethanol at-15° C. Each frozen sample weighed 1.00 g. When all the ice wasdissolved into the ethanol (5 hours), the product was transferred to avacuum chamber in order to remove residual ethanol. This produced asample, i.e., a network of carrier material, that disintegrated rapidlyin 1 to 5 seconds when taken orally. Each of the processed samplesweighed 50 mg.

EXAMPLE 36 Preparation of a Placebo Carrier Matrix by Solid-StateDissolution

Gelatin (pharmaceutical grade) (20 g), glycine (50 g), and aspartame(2.5 g) were dissolved in 940 of water. The resulting solution wascarefully transferred into 1 ml size molds. A mold consisted of apolyvinyl chloride (p.v.c.) sheet with 50 cylindrical depressions (18 mmdiameter and 5 mm deep). The p.v.c. sheet and its contents were cooledwith dry ice for about one hour. At the end of one hour, the frozencontents were weighed and immersed into 5000 g of absolute ethanol at-15° C. Each frozen sample weighed 1.00 g. When all the ice wasdissolved into the ethanol (5 hours), the product was transferred to avacuum chamber in order to remove residual ethanol. This produced asample, i.e., a network of carrier material, that disintegrated rapidlyin 1 to 5 seconds when taken orally. Each of the processed samplesweighed 50 mg.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention.

We claim as our invention:
 1. A method for preparing a porous unitdosage form comprising the steps of:(a) dispersing or dissolving amatrix forming agent in a first solvent; (b) solidifying a unit volumeof the dispersion or solution; (c) contacting the solidified unit volumewith a second solvent, the first solvent in the solidified unit volumebeing substantially miscible with the second solvent, the solidificationpoint of the first solvent being higher than the solidification point ofthe second solvent, the second solvent being at a temperature at orhigher than the solidification point of the second solvent and at atemperature at or lower than the solidification point of the firstsolvent, the matrix forming agent being substantially insoluble in thesecond solvent, the contacting being sufficient to substantially removethe first solvent from the solidified unit volume thereby yielding aunit dosage form that is substantially free of the first solvent; and(d) recovering the unit dosage form, the matrix forming agent beingpresent in the dispersion or solution in an amount sufficient to form amatrix upon the substantial removal of the first solvent.
 2. The methodaccording to claim 1, wherein the first solvent is water and the secondsolvent is a water miscible alcohol.
 3. The method according to claim 1,wherein the matrix forming agent is selected from the group consistingof gelatins, dextrins, soy proteins, wheat proteins, psyllium seedproteins, gums, alginates, polysaccharides, carboxymethylcellulose,carrageenans, dextrans, pectins, polyvinylpyrrolidone, gelatin-acaciacomplexes, mannitol, dextrose, lactose, galactose, cyclodextrin, konjacflour, cellulose, sodium starch glycolate, polydextrose,hydroxyethylcellulose, amino acids having 2 to 12 carbon atoms, cornsyrup solids, chitosan, rice flour, wheat gluten, soy fiber proteins,potato proteins, papain, horse radish peroxidase and mixtures thereof.4. The method according to claim 3, wherein at least one of the matrixforming agents is selected from the group consisting of gelatin, pectin,mannitol and glycine.
 5. The method according to claim 2, wherein thealcohol is at a temperature from about 0 to -100° C.
 6. The methodaccording to claim 1, wherein the matrix forming agent is present in aconcentration of about 0.1% to 15% by weight of the dispersion orsolution.
 7. The method according to claim 1, comprising the additionalstep of:(c) evaporating residual second solvent from the unit dosageform.
 8. The method according to claim 1, wherein the dispersion orsolution also contains an active agent to be delivered, the active agentbeing substantially insoluble in the second solvent.
 9. The methodaccording to claim 1, comprising the additional step of:(e) contactingthe unit dosage form with an active agent to be delivered such that theactive agent is dispersed through the matrix.
 10. The method accordingto claim 8 wherein the active agent is a bioactive agent.
 11. The methodaccording to claim 9 wherein the active agent is an effective unitdosage amount of a bioactive agent.
 12. The method according to claim 1,wherein the matrix forming agent comprises gelatin, mannitol andglycine.
 13. The method according to claim 1 wherein the delivery matrixadditionally comprises an active agent.